Phthalides and naphthalides

ABSTRACT

This invention relates to a process of preparing phthalein indicator dyes including phthalides and naphthalides derived from certain hydroxy-substituted carbocyclic aryl compounds, such as phenols, and from certain N-heterocyclic aryl compounds, such as indoles, and to a process of preparing novel intermediates useful therein. According to the present invention, the selected carbocyclic compound or the selected N-heterocyclic compound is reacted with phthaladehydic or naphthalaldehydic acid to form the corresponding (na)phthalidyl adduct which is treated with an oxidizing agent to yield the subject intermediates. To prepare the indicator dye, the intermediate, i.e., the oxidation product thus obtained is then reacted with a carbocyclic or heterocyclic aryl compound to yield the corresponding indicator dye. The oxidation products comprising the novel intermediates of the present invention may be dehydro or hydrated (na)phthalidyl adducts.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of copending application Ser. No. 617,300filed Sept. 29, 1975, which is a continuation-in-part of applicationSer. No. 446,732 filed Feb. 28, 1974, now U.S. Pat. No. 3,941,807,which, in turn, is a continuation-in-part of application Ser. No.108,662 filed Jan. 21, 1971, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a novel method of preparing indicator dyes, tonovel intermediates useful in the preparation of the dyes and to thepreparation of the intermediates.

2. Description of the Prior Art

Dyes which undergo a change in spectral absorption characteristics inresponse to a change in pH are well known in the art and are frequentlyreferred to as indicator or pH-sensitive dyes. Typically, these dyeschange from one color to another, from colored to colorless or fromcolorless to colored on the passage from acidity to alkalinity or thereverse and are commonly employed in analytical chemical procedures tomeasure changes in pH value. Among the indicator dyes most widely usedis the group derived from phthaleins as exemplified by phenolphthalein,thymolphthalein, o-cresolphthalein and 1-naptholphthalein.

Various methods are known in the art for preparing phthalein indicatordyes. In one of the more conventional procedures, phenols, such asthymol, o-cresol, and phenol itself are reacted with phthalic anhydrideat elevated temperatures in the presence of a suitable catalyst such aszinc chloride or sulfuric acid to yield the corresponding symmetrical,i.e., di-phenol phthalein. Di-indole phthaleins also have been preparedby simple condensation usually in the presence of an acid catalyst andby other methods, such as, reacting magnesium indyl bromide withphthalyl chloride.

Another method of synthesizing indole phthaleins is disclosed in BritishPat. Nos. 1,160,940; 1,161,386; 1,161,387; and 1,162,771, whichcomprises reacting an indole with phthalic anhydride in the presence ofa metal halide, e.g., aluminum chloride to yield a keto-acidintermediate which is subsequently reacted with a second aromaticcompound, the same or different, in the presence of an acid condensingagent to yield the desired insole phthalein. Using this method bothsymmetrical and unsymmetrical compounds may be prepared by selectingrespectively, as the second aromatic compound, an indole which is thesame or an indole which is different from the starting indole initiallyreacted with the anhydride. Where it is desired to produce a mixedindole phthalein containing an indole radical and a second radicalderived from a different aromatic compound such as carbazole or anilinethe keto-acid intermediate may be formed by reaction of the indole,carbazole or other appropriate compound with phthalic anhydride followedby condensation of the intermediate with the second aromatic compound toyield the desired mixed indole indicator dye.

These prior methods of preparing phthaleins, though useful insynthesizing a large number of compounds, are accompanied by certaindrawbacks. The simple condensation reactions and the Grignard reactionsare not useful with all starting materials. Some phenols and indoleswill not react under the condensation conditions conventionallyemployed. Moreover, these synthetic methods generally are limited to theproduction of symmetrical compounds, i.e., di-phthalides containing twoindole or two phenol radicals that are identical. While the method ofthe aforementioned British patents is useful for producing symmetricaland unsymmetrical indole phthaleins and also mixed indole indicatordyes, the more sensitive indole derivatives, when used as startingmaterials, tend to decompose under the vigorous reaction conditionsencountered in the presence of the aluminum chloride catalyst.

It is known from the work of Brubaker, et al., J. Amer. Chem. Soc., 49,2279 (1927) that o-phthalaldehydic acid condenses with phenol andcertain substituted phenols having a free para-position to yield thepara-condensation products. These compounds were prepared by mixingequimolar proportions of phenol and phthalaldehydic acid and then addinga suitable condensing acid, such as sulfuric acid, while maintaining thereaction temperature below about 30° C.

As reported by Norland, et. al., ibid., 82, 5143 (1960), phthalaldehydicacid and indoles will condense to yield phthalidylindoles and water whenthe two reactants are fused together at temperatures of 120° to > 200°C. If the 3-position of the indole is free, then 3-phthalidylindoles areformed. If the 3-position is blocked or if the 1- and 3-positions areblocked, then 1-phthalidylindoles and 2-phthalidylindoles are formed,respectively.

Rees, et al., J. Chem. Soc., pp. 680-687 (1965) observed that forreaction with phthalaldehydic acid the 3-substituted indoles and the1,3-disubstituted indoles generally require the vigorous fusionconditions used by Norland et al., but found that indoles having a free3-position will react with phthalaldehydic acid under milder conditions.Indole and its 2-phenyl, 2-methyl, 7-methyl and 1,2-dimethyl derivativeswere reported to react in hot benzene to yield the corresponding3-phthalidyl indoles which results were attributed to intramolecularacid catalysis. In solution phthalaldehydic acid exists in the cyclicform, 3-hydroxyphthalide, which is in rapid equilibrium with theopen-ring form, o-formylbenzoic acid. Presumably, the indole reacts withthe aldehyde form and the carboxyl group ortho to the aldehyde groupfunctions as an intramolecular acid catalyst. The authors observed thatreactions with indole and 2-methyl indole also were catalyzed by anexternal acid catalyst, such as toluene-p-sulfonic acid, and also that asecond mole of indole could be added to 3-phthalidylindole by openingthe lactone ring with alkali and treating the resulting salt with asecond mole of indole.

Rees et al. in further studies, ibid., pp. 687-91 (1965), reported thatthe condensation of phthalaldehydic acid could be extended to pyrrolesand found that phthalaldehydic acid reacted with pyrrole and2,5-dimethyl pyrrole in boiling benzene in the absence of an externalcatalyst to give high yields of 2-phthalidyl-pyrrole and3-phthalidyl-pyrrole, respectively. In these reactions, it was observedthat pyrrole tended to substitute in the 2-position when possible toyield the 2-phthalidyl derivative. In a further extension of thereactions, the authors found that naphthalaldehydic acid, though lessreactive than phthalaldehydic acid, behaved in a similar manner andcould be condensed with indole under fusion conditions to yield3-naphthalidylindole.

It has now been found that certain phthalidyl-substituted phenols,naphthols, indoles and pyrroles and the corresponding naphthalidylderivatives may be oxidized to yield novel intermediates which willcondense readily with another mole of the same aromatic compound as usedin the initial condensation reaction or a different aromatic compound,to yield a phthalide or naphthalide indicator dye.

SUMMARY OF THE INVENTION

It is, therefore, the primary object of the present invention to providea novel method of synthesizing phthalein indicator dyes.

It is another object of the present invention to provide a method ofsynthesizing phthalide and naphthalide indicator dyes which may besymmetrical, unsymmetrical or mixed indicator dyes.

It is a further object of the present invention to provide novelintermediates useful in the preparation of such dyes and to provide amethod for preparing the intermediates.

Other objects of this invention will in part be obvious and will in partappear hereinafter.

The invention accordingly comprises the process involving the severalsteps and the relation and order of one or more of such steps withrespect to each of the others and the product possessing the features,properties and the relation or elements which are exemplified in thefollowing detailed disclosure and the scope of the application of whichwill be indicated in the claims.

According to the present invention, there is provided a novel method ofpreparing phthalein indicator dyes that is generally applicable to thesynthesis of phthalides and naphthalides of certain hydroxy-substitutedcarbocyclic aryl compounds, namely, phenols and benzphenols (i.e.,1-naphthols) and certain N-heterocyclic aryl compounds, namely, pyrrolesand benzpyrroles (i.e., indoles). The present method comprises (1)reacting a hydroxy-substituted carbocyclic compound selected from aphenol and a 1-naphthol or an N-heterocyclic aryl compound selected froman indole and a pyrrole with phthalaldehydic or naphthaldehydic acid toform the corresponding (na)phthalidyl-substituted intermediate, (2)oxidizing the intermediate and (3) reacting the oxidation product withan aromatic compound selected from carbocyclic aryl and heterocyclicaryl to form the complete indicator dye. As used herein, the expression"(na)phthalidyl" is intended to denote either the correspondingphthalidyl- or naphthalidyl-substituted intermediate depending upon theselection of phthalaldehydic or naphthalaldehydic acid.

Since the reaction conditions are comparatively mild, the presentinvention allows greater latitude in the selection of startingmaterials. For example, the indole derivatives to be initially reactedwith the acid are not limited to the more stable compounds but mayinclude alkali and acid sensitive compounds as well. The presentinvention also allows greater latitude in the indicator dyes that may beproduced. Novel intermediates are obtained as the oxidation product ofstep (2) which may be reacted with any of various aromatic compounds instep (3) to form a complete dye so that both symmetrical andunsymmetrical phthalides and naphthalides and also, mixed indicatordyes, such as phthalides and naphthalides containing, for example, onephenol radical and one indole radical, may be readily synthesized.

For a fuller understanding of the nature and objects of the presentinvention reference should be had to the following detailed description.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Specifically, the method of the present invention comprises:

(1) reacting a compound selected from (a) a hydroxy-substitutedcarbocyclic aryl compound having a free position para to the hydroxygroup selected from a phenol and a 1-naphthol and (b) an N-heterocyclicaryl compound having hydrogen substituted on the nitrogen atom selectedfrom an indole having a free 3-position and a pyrrole having a free2-position with a compound selected from phthalaldehydic andnaphthalaldehydic acid to form a compound having the formula: ##STR1##wherein A is selected from p-hydroxyphenyl, p-hydroxynaphthyl,indol-3-yl and pyrr-2-yl and X represents the carbon atoms necessary tocomplete a ring-closing moiety selected from phthalide and naphthalide;

(2) converting the last-named compound by oxidation to a compoundselected from ##STR2## and mixtures thereof wherein A' is selected from##STR3## and A and X have the same meaning as above; and

(3) reacting said last-named compound with an aromatic compound selectedfrom a carbocyclic aryl compound and a heterocyclic aryl compound toform an indicator dye of the formula: ##STR4## wherein B is selectedfrom carbocyclic aryl and heterocyclic aryl and A and X have the samemeaning as above.

The above reaction scheme is illustrated below wherein A" represents thestarting phenol, naphthol, indole or pyrrole which ultimately comprisesthe A radical of the indicator dye and B' represents the carbocylic arylor heterocyclic aryl compound which ultimately comprises the B radicalof the indicator dye and X represents the carbon atoms necessary tocomplete the phthalide or naphthalide moiety. ##STR5##

This reaction sequence is further illustrated below under the preferredanhydrous conditions using as specific reactants, indole andphthalaldehydic acid to produce 3,3-di-(indol-3-yl) phthalide. ##STR6##

Typical of the indicator dyes that may be prepared according to thepresent invention are those represented by the following formula:##STR7## wherein A is a radical selected from p-hydroxyphenyl,p-hydroxynaphthyl, indol-3-yl and pyrr-2-yl, the N atoms of said indolyland pyrryl radicals being substituted with hydrogen; B is a radicalselected from carbocyclic aryl and heterocyclic aryl; and X representsthe carbon atoms necessary to complete a ring-closing moiety selectedfrom phthalide and naphthalide.

In the above formula, the B radical may be carbocyclic aryl of thebenzene or naphthalene series, preferably benzene or naphthalenecontaining a para substituent, such as hydroxy, or it may beheterocyclic aryl containing O, N, S, P and combinations thereof,preferably N-heterocyclic aryl, such as indole, pyrrole or carbazole.

The A and/or B radical and/or the ring-closing moiety of the indicatordyes represented above may contain one or more substituents in additionto those specified as may be readily selected by those skilled in theart to achieve certain desired properties.

Typical substituents include branched or straight chain alkyl, such as,methyl, ethyl, isopropyl, n-butyl, t-butyl, hexyl, octyl, dodecyl,hexadecyl, octadecyl and eicosanyl; aryl, such as, phenyl,2-hydroxyphenyl, 2-hydroxy-4-dodecyloxyphenyl, and naphthyl; alkaryl,such as, benzyl, phenethyl, phenylhexyl, p-octylphenyl, p-dodecylphenyl;alkoxy, such as, methoxy, ethoxy, butoxy, 1-ethoxy-2-(β-ethoxyethoxy),dodecyloxy and octadecyloxy; aryloxy, such as phenoxy, benzyloxy,naphthoxy; alkoxyalkyl, such as methoxyethyl, dodecyloxyethyl; halo suchas, fluoro, bromo, and chloro; trifluoroalkyl, such as trifluoromethyl,mono- and bis-trifluoromethyl carbinol; sulfonamido (--NH--SO₂ --R₁wherein R₁ is a hydrocarbon group containing up to 20 carbon atoms andmay be alkyl; aryl, such as, phenyl and naphthyl; aralkyl and alkaryl,particularly phenyl-substituted alkyl and alkyl-substituted phenyl);sulfamoyl (--SO₂ --NH--R₂ wherein R₂ has the same meaning as R₁);sulfonyl (--SO₂ --R₃ wherein R₃ has the same meaning as R₁); acyl andits derivatives ##STR8## wherein R₄ may be hydrogen or a hydrocarbongroup as defined in R₁); aminomethyl (--CH₂ --NR₅ R₆ wherein R₅ and R₆each have the same meaning as R₄); amido ##STR9## wherein R₇ and R₈ eachhave the same meaning as R₄) sulfo; cyano; nitro; amino including mono-and disubstituted amino, e.g., N-ethyl amino and N,N'-dimethylamino;carboxy; and hydroxyl.

In addition to the above, the substituent may comprise a fused ringbonded to adjacent atoms of the aromatic nucleus. For example, theindoles, pyrroles, phenols and 1-naphthols comprising one or both of theA and B radicals may contain as a substituent a cycloaliphatic or anaromatic ring usually having 5 or 6 members, carbocyclic or heterocyclicand substituted or unsubstituted, bonded to adjacent carbon atoms of thebasic compound, e.g., ##STR10## wherein R° is, e.g., --OH or --COOH##STR11## wherein R° is, e.g., --OH or --COOH

As mentioned previously, the indicator dyes produced in accordance withthe present invention may be symmetrical, i.e., di-phthalides ordi-naphthalides in which instance the B radical would be identical tothe A radical, or they may be unsymmetrical or mixed indicators. Whenunsymmetrical, the A radical and B radical would be derived from thesame aromatic compound such as, indole, but each radical would containdifferent substituents or the same substituents in different positionsor one radical would be substituted and the other unsubstituted. Theterm "mixed indicator" is intended to denote indicator dyes where the Aradical and B radical are derived from different aromatic compounds, forexample, one from indole and the other from phenol.

In a preferred embodiment, the method of synthesizing the subjectoxidation products and the method of synthesizing indicator dyestherefrom comprises:

(1) reacting in substantially equimolar proportions in an inert organicliquid solvent at a temperature between about 20° C. and 120° C., (a) acompound selected from ##STR12## wherein R¹ is selected from hydrogen,alkoxy containing 1 to 3 carbon atoms and alkyl containing 1 to 3 carbonatoms; R² is selected from hydrogen, hydroxy, carboxy, sulfonamido(--NH--SO₂ --R₁), sulfamoyl (--SO₂ --NH--R₂), o-hydroxyphenyl,bis-trifluoromethylcarbinol, methoxy, alkyl containing 1 to 16 carbonatoms; R³ is selected from hydrogen, alkoxy containing 1 to 18 carbonatoms and alkyl containing 1 to 3 carbon atoms; R⁴ is selected fromhydrogen, hydroxy and carboxy; R⁵ is selected from hydrogen and alkoxycontaining 1 to 18 carbon atoms; R⁶ is selected from hydrogen, phenyl,alkyl containing 1 to 3 carbon atoms, and alkoxy containing 1 to 18carbon atoms; R⁷ is selected from hydrogen, phenyl, o-hydroxyphenyl andalkyl containing 1 to 3 carbon atoms and R⁸ is selected from hydrogen,cyano, carboxy, halo, trifluoromethyl, sulfonyl (--SO.sub. 2 --R₃) andalkoxy containing 1 to 18 carbon atoms with (b) an aldehydic acidselected from phthalaldehydic acid, unsubstituted or substituted in oneof the 4- or 7-positions with carboxy and naphthalaldehydic acid,unsubstituted, to form the corresponding adduct having the formula:##STR13## wherein A is a radical selected from p-hydroxyphenyl,p-hydroxynaphthyl, pyrr-2-yl and indol-3-yl corresponding to said (i),(ii) (iii) and (iv), respectively, and X represents the carbon atomsnecessary to complete a ring-closing moiety selected from phthalide,unsubstituted or substituted in the 4- or 7-position with carboxy, andnaphthalide, unsubstituted; and

(2) reacting said adduct with a quinone selected from chloranil,o-chloranil and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in a molarratio of about 1.1 to 1.5 moles of guinone per 1.0 mole of adduct in aninert organic liquid solvent at a temperature between about 20° C. and200° C. to form the corresponding oxidation product.

To prepare the indicator dye product, the oxidation product of step (2)is reacted with a compound selected from (i), (ii), (iii) and (iv) asdefined in (a) above in substantially equimolar proportions in an inertorganic liquid solvent at a temperature between about 20° C. and 120° C.in the presence of an acid catalyst to form the corresponding3,3-disubstituted phthalide or naphthalide, ##STR14## wherein A and Beach is a radical selected from p-hydroxyphenyl, p-hydroxynaphthyl,pyrr-2-yl, and indol-3-yl corresponding to said (i), (ii), (iii) and(iv), respectively, and X represents the carbon atoms necessary tocomplete a ring-closing moiety selected from phthalide, unsubstituted orsubstituted in the 4- or 7-position with carboxy and naphthalide,unsubstituted.

In a particularly preferred embodiment, the process of the presentinvention are employed in the synthesis of phthalides and naphthalideswherein the radicals A and B of the dye product are bothp-hydroxyphenyl, p-hydroxynaphthyl, etc., either symmetrical orunsymmetrical and especially such dyes and dye intermediates wherein theR² group(s) forms a 5-, 6- or 7-membered intramolecular hydrogen-bondedring with the functional --OH of the p-hydroxycarbocyclic aryl radicalor the --NH-- of the N-heterocyclic aryl radical and which contains aheteroatom selected from O, N and S. Preferably, the heteroatom hasattached to it a proton more acidic than the proton on the --OH or--NH-- and ionizes in basic solution to a negative charge to form theintramolecular hydrogen bond with the adjacent --OH or --NH--. Examplesof such groups found particularly useful in preparing high pKa indicatordyes are carboxy, hydroxy, ortho-hydroxyphenyl, bis-trifluoromethylcarbinol, sulfonamido and sulfamoyl. Such phthalide and naphthalideindicator dyes include those where at least one of the R² groups of thedi-phenol, di-naphthol, di-pyrrole and di-indole dyes is ahydrogen-bonding group, for example, di-phenol indicators wherein R² onone or both of the phenolic radicals is a hydrogen-bonding group;di-naphthol indicators wherein R² on one of the naphtholic radicals is ahydrogen-bonding group and R⁴ is hydrogen and on the second naphtholicradical, R² is hydrogen; di-pyrrole indicators wherein R² on one or bothof the pyrr-2-yl radicals is a hydrogen-bonding group; and di-indoleindicators wherein R² on one of the indol-3-yl radicals is ahydrogen-bonding group, and R⁷ is hydrogen and on the second indol-3-ylradical, R⁷ is hydrogen and R² is a hydrogen-bonding group and R⁸ ishydrogen, alkoxy or an electron-withdrawing group, i.e., a group havinga positive sigma value as defined by Hammett's Equation, such as,carboxy, cyano, halo, sulfonyl and trifluoromethyl.

Examples of specific indicator dyes that may be prepared according tothe present invention include: ##STR15##

The novel intermediates of the present invention are obtained as theproduct(s) of step 2 of the present method as shown in the foregoinggeneral reaction scheme and may be represented by the formulae:##STR16## wherein A' is selected from ##STR17## A is selected from##STR18## and X represents the atoms necessary to complete aring-closing moiety selected from phthalide and naphthalide. It will beappreciated that the above intermediates may contain one or moresubstituents as ultimately desired in the complete dye, such as thoseenumerated above.

Preferred intermediates are those of formulas (IIa) and (IIIa).##STR19## where A' is selected from ##STR20## A is selected from##STR21## wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ and X have the samemeaning given above. As discussed above, in a particularly preferredembodiment, R² in the above formulas is a hydrogen-bonding group and R³,R⁵, R⁶ and R⁸ are hydrogen or a group for controlling diffusibility ofthe dye product, preferably, an alkoxy group containing 1 to 18 carbonatoms. R⁴ and R⁷ are hydrogen and R¹ is hydrogen, alkoxy or alkyl. Inthe indole intermediates another particularly preferred embodimentcomprises compounds wherein R⁸ is an electron-withdrawing group, asdiscussed above, R² is hydrogen or a hydrogen-bonding group and R⁷ ishydrogen or R² is hydrogen and R⁷ is o-hydroxyphenyl. In theseintermediates, the hydroxy and carboxy substituents adjacent the --OH or--NH-- may be blocked with alkyl, e.g., having 1 to 6 carbon atoms, suchas, --COOCH₃.

When the oxidation reaction is carried out under anhydrous conditions,the dehydro intermediate of Formula (II) is obtained and may beisolated, if desired, and reacted with the second aromatic compound toform the complete dye. This intermediate may be readily hydrated toyield the intermediate of Formula (III). Mixtures of the two compoundsas represented by Formulae (II) and (III) may be obtained when traceamounts of water are present during oxidation or when the compound ofFormula (II) is exposed to atmospheric moisture upon standing. Thecompound of Formula (III) also may be isolated, if desired, beforefurther reaction. Both intermediates react readily with the aromaticcompound, and the product of step 2 may be reacted further withoutisolating the individual compounds even though the product may be amixture of the dehydro and hydrated intermediates. Preferably, however,the oxidation reaction is conducted under anhydrous conditions to yieldthe dehydro intermediate. If it is desired to use the hydratedintermediate for further reaction, it is preferred to hydrate thedehydro compound rather than carrying out the oxidation in the presenceof water to yield hydrated intermediate directly.

Specific examples of novel intermediates of the present inventioninclude: ##STR22##

In carrying out the present method, the starting materials, i.e., thehydroxy substituted carbocyclic compound or N-heterocyclic compound andthe (na)phthalaldehydic acid may be reacted in a solvent at roomtemperature or elevated temperature as described in the aforementionedreference of Rees et. al. In the present invention, it is sometimespreferred to react the starting materials in the presence of an externalacid catalyst, for example, an organic acid catalyst, such astoluene-p-sulfonic acid, trifluoroacetic acid and trichloroacetic acid.The reaction temperature may vary over a relatively wide range from roomtemperature, i.e., about 20° C. up to elevated temperatures of about120° C. which may be readily determined for the particular reactants. Toachieve practical reaction rates, it is preferred to conduct thereaction at elevated temperatures but below temperatures wheredecomposition of starting material and/or side reactions and by-productstend to occur. The solvent used may be any of the inert organic liquidscommonly employed for this purpose, such as, glacial acetic acid,ethanol, propanol, petroleum ether, hexane, heptane, cyclohexane,toluene, methylene chloride, and benzene. Ordinarily, a polar solvent isselected when an external acid catalyst is employed and a non-polarsolvent when the reaction is conducted in the absence of an externalacid catalyst.

The (na)phthalidyl intermediate of the phenol, naphthol, indole orpyrrole thus produced is oxidized by dehydrogenation to selectivelyremove the hydrogen from the 3-position of the (na)phthalidyl portionand to remove the hydrogen from the hydroxy group of the phenol (ornaphthol) or from the 1-position, i.e., N atom of the indole (orpyrrole) thereby converting the single bond connecting the two portionsof the molecule to a double bond. Quinones have been found particularlyuseful for this purpose including, for example, ortho- andpara-quinones, such as dicyanodichloroquinone, chloranil, andortho-chloranil. It has been found that these materials will selectivelyremove the hydrogens as desired and without oxidizing the compoundfurther. The solvent used in the oxidation step may be any inert organicliquid that does not react with the oxidizing agent, such as dioxane,toluene, benzene, dichloromethane and hexane. The temperature employedmay vary widely and generally ranges between about 20° C. and 200° C. Asin the initial condensation step, the oxidation step is preferablyconducted at elevated temperatures that may be readily selected toachieve a practical reaction rate without by-product formation.

Subsequent to the oxidation step, a second aromatic compound iscondensed with the oxidation product to yield the complete indicatordye. The second condensation reaction, like the initial condensation maybe carried out in a suitable solvent at room or elevated temperature of20° to 120° C. preferably in the presence of an acid catalyst such asphosphorous oxychloride, boron trifluoride (e.g. in benzene or ether)and other Lewis acids, such as zinc chloride and the catalystsenumerated above, i.e., toluene-p-sulfonic acid, trifluoroacetic acidand trichloroacetic acid. The inert organic solvent used may be any ofthose commonly employed in condensation reactions such as the particularsolvents mentioned above for use in the initial condensation.

The starting materials preferably are used in equimolar quantities andin the oxidation step, the oxidizing agent and (na)phthalidylintermediate may be used in equimolar quantities but preferably, theoxidizing agent is used in excess to ensure completion of the reaction.A ratio of 1.1 to 1.5 moles of oxidizing agent to 1.0 mole ofintermediate has been found satisfactory. In the second or finalcondensation, the oxidized intermediate and the second aromatic compoundselected to form the complete dye preferably are used in equimolarproportions.

As the starting materials, any phenol or 1-naphthol may be employedprovided it has a free 4-position, i.e., it is unsubstituted on thecarbon atom para to the phenolic hydroxy group, so that the hydrogenwill be displaced to yield the corresponding 4-(na)phthalidylintermediate in the initial condensation with the acid. Likewise, anyindole or pyrrole starting material may be employed provided that thesecompounds have a free 3-position and a free 2-position, respectively, sothat the corresponding 3-(na)phthalidylindole and2-(na)phthalidylpyrrole will be produced in the initial condensationreaction. The indoles and pyrroles each should also have a free1-position, i.e., the nitrogen atoms of these compounds should besubstituted with hydrogen. Other than the necessary free positionsdiscussed above, the starting materials may contain one or moresubstituents as may be desired in the final indicator dye provided anysubstituent positioned adjacent the condensation site and tending tobond internally with the dehydro intermediate is protected with ablocking group that may be removed subsequent to condensation of theintermediate with the second aromatic compound. For example, the carboxygroup of 2-carboxyindole may be protected as an alkyl ester and thealkyl blocking portion removed after the complete dye is formed byalkaline hydrolysis. Similarly, a hydroxy-substituted aryl or alkylgroup in the 2-position of an indole may be protected as an alkyl etherand the alkyl blocking portion removed by catalytic hydrogenation.

For purposes of nomenclature, the following illustrates the numbering ofthe hydroxy-substituted carbocyclic compounds and N-heterocycliccompounds used as the starting materials in the present method.##STR23##

Likewise, the aldehydic acid reacted with the hydroxy-substitutedcarbocyclic or N-heterocyclic compound may be a substitutedphthalaldehydic acid or naphthaldehydic acid, such as,carboxy-substituted compounds, e.g., 4-carboxy-phthalaldehydic acid and7-carboxy-phthalaldehydic acid and sulfonamido-substituted compounds,e.g., 6-hexadecylsulfonamido-naphthalaldehydic acid.

The aromatic compound condensed with the oxidized intermediate to formthe complete dye may be a carbocyclic aryl compound of the benzene ornaphthalene series, or it may be a heterocyclic aryl compound containingO, N, S, or P or combinations thereof. The heterocyclic compound ispreferably N-heterocyclic derived from, e.g., indole, pyrrole orcarbazole, though it may be derived from, e.g., N-benzylindoline. In apreferred embodiment, the starting materials employed in the synthesisof the oxidized intermediates of the present invention and the aromaticcompound condensed with the intermediate are the phenols, 1-naphthols,pyrroles and indoles designated above as i, ii, iii and iv,respectively.

The following Examples are given to further illustrate the presentinvention and are not intended to limit the scope thereof.

EXAMPLE 1 Preparation of the Compound of Formula (21)

A mixture of 6.0 g. (0.0372 mole) of 7-carboxyindole and 7.5 g. (0.0372mole) of naphthaldehydic acid in 38 ml. of glacial acetic acid washeated to reflux and stirred mechanically. To the solution was addeddropwise, 38 ml. of 12% toluene-p-sulfonic acid-acetic acid. Animmediate precipitation of product began and the mixture was refluxedfor five minutes. The mixture was cooled to room temperature, filtered,and the 3-naphthalidylindole intermediate washed with 50 ml. of aceticacid. The solid was then stirred in 100 ml. of acetone, filtered anddried to give 12.8 g. (86% by weight yield) of a white crystallinesolid, 239°-240° C. melting range.

A mixture of 11.0 g. (0.028 mole) of the intermediate prepared above and140 ml. of dioxane was refluxed with stirring under nitrogen. To thesolution was added 7.3 g. (0.032 mole) of2,3-dichloro-5,6-dicyano-1,4-benzoquinone and the refluxing continuedfor 3.5 hours. The mixture was cooled to room temperature and the pinksolid comprising oxidized intermediate was collected by suctionfiltration. The solid was extracted twice by boiling in 125 ml. ofacetone for 5 to 10 minutes. The solid was then heated in 125 ml. ofethanol and the white solid collected. Weight 7.2 g. (78% by weightyield).

A mixture of 0.40 g. (1.2 m mole) of oxidized intermediate and 0.51 g.(1.2 m mole) of 7-hexadecylsulfonamidoindole in 5 ml. of glacial aceticacid was heated to 65° C. with stirring. To the mixture was added 5 ml.of 12% toluene-p-sulfonic acid-acetic acid over a five-minute period.The solution turned an intense purple color. The heating was continuedfor 15 minutes at 65° C. and cooled to room temperature. The solutionwas poured into 20 ml. of water containing 3 ml. of concentrated NH₄ OH.The precipitate was collected and dried. Recrystallization of 0.8 g. ofthis material from methanol-water gave 0.66 g. (77% by weight yield) oftitle compound, melting range 216°-217° C.

Steps 1 and 2 of the foregoing procedure were repeated using2-carboxy-benzaldehyde (o-formylbenzoic acid), the open-ring form ofphthalaldehydic acid.

8.05 g. (0.05 mole) of 7-carboxyindole and 7.5 g. (0.05 mole) of2-carboxybenzaldehyde were heated under reflux in 90 ml. of xylene in a500 ml. roundbottom flask with stirring for 8 hours. The mixture wascooled to room temperature and allowed to stand overnight. The productwas collected by suction filtration, washed with benzene and dried invacuo at 60° C. Wgt.= 13.0 g. The product was recrystallized fromethanol (˜300 ml.). After refrigeration, the product was collected bysuction filtration. Wgt.= 8.2 g., melting range 250°-2° C. The ethanolwas evaporated to ˜50 ml. and a second crop of material collected. Wgt.=2.0 g., melting range 248°-50° C. Overall yield 10.2 g., (67% by weightyield). The material was thoroughly dried in vacuo (60° C.).

3.2 g. (0.011 mole) of the product obtained above and 2.7 g. (0.012mole) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone were heated in 60 ml.of freshly opened analytical grade dioxane at 60° C. for 24 hours undernitrogen with stirring. The mixture was cooled to room temperature andthe hydroquinone (2.05 g.) removed by filtration. The filtrate wasconcentrated to a volume of 10 ml. in vacuo and an additional 0.4 g. ofhydroquinone collected. The product was precipitated by the addition ofbenzene (60 ml.) to the filtrate. Wgt.= 1.9 g. Concentration of thefiltrate to a volume of 20 ml. followed by the addition of 50 ml. ofbenzene furnished an additional 1.0 g. of product.

Th hydroquinone collected was compared to and found to be identical witha standard sample of 2,3-dichloro-5,6-dicyano-1,4-hydroquinonesubstantiating the removal of the two hydrogens from thephthalidyl-substituted carboxyindole to yield a dehydro product underanhydrous conditions. The dehydro product upon initial precipitation wasyellow and was observed to become substantially colorless upon standingin the presence of atmospheric moisture. The colorless product formedupon standing on the basis of molecular weight determination was foundto correspond to the hydrated form of the dehydro product as evidencedby a difference of 18 in molecular weight. Further studies revealed thata mixture of dehydro and hydrated products can be obtained in theoxidation step when moisture is present, for example, when trace amountsof water is present in the dioxane solvent. Upon further reaction withorthohydroxyphenylindole, the dehydro and hydrated intermediates showedsubstantially equivalent reactivity in the formation of the completedye.

EXAMPLE 2

The product of Example 1 was prepared in the same manner described aboveexcept that o-chloranil (0.029 mole) was substituted fordichlorodicyanoquinone as the oxidizing agent.

EXAMPLE 3 Preparation of the Compound of Formula (97)

A solution of 10.0 g. (0.05 mole) of naphthaldehydic acid and 8.9 g.(0.05 mole) of 2,6-diisopropylphenol in 80 ml. of 12% p-toluene sulfonicacid in acetic acid was refluxed for 8 hours. The solution was cooledand the product began to precipitate out. The mixture was poured onto200 g. of ice and stirred. The white solid was filtered and dissolved in200 ml. of hot ethanol. Water was added slowly until the solution wasturbid and cooled and the solid collected by filtration and dried togive 15.0 g. (83.5% by weight yield) of solid, melting range 185°-187°C. (decomposition).

5.0 g. (0.0139 mole) of the intermediate prepared above was dissolved in100 ml. of methylene chloride. To this solution was added 3.4 g. (10%excess) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The reactionmixture was refluxed under a nitrogen atmosphere for 4 hours. Themixture was cooled and the 2,3-dichloro-5,6-dicyano-1,4-hydroquinonefiltered off. The methylene chloride was evaporated under vacuum and theoil dissolved in ethanol with heating. The ethanol was evaporated undervacuum and the solid collected as an orange powder 4.5 g. (90% by weightyield), melting range 38° -40° C.

3.2 g. (0.0092 mole) of the oxidized intermediate prepared above wasdissolved in 25 ml. of phosphorous oxychloride together with 2.0 g. of2-isopropyl phenol. The resulting mixture was stirred for 6 hours atroom temperature and then was added to a mixture of 100 g. of ice, 100ml. of water and 2 ml. of conc. hydrochloric acid. The product wasextracted with 200 ml. of ether, dried over anhydrous calcium chloride,and the ether evaporated. The resulting red oil was placed in hexane anda pink solid formed with recrystallization from 100 ml. of ethanol and20 ml. of water to yield 3.1 g. (70% by weight yield) of the titlecompound, melting range, 225°-227° C.

EXAMPLE 4 Preparation of the Compound of Formula (124)

Example 3 was repeated except that 2-hexadecyl-1-naphthol was reactedwith the oxidized naphthalidyl-substituted 2,6-diisopropyl phenolintermediate by adding 15 ml. of phosphorus oxychloride to 0.5 g.(0.0014 mole) of oxidized intermediate and 0.51 g. (0.0014 mole) of2-hexadecyl-1-naphthol. The resulting mixture was stirred at roomtemperature for 6 hours and then poured onto a mixture of 25 g. of ice,25 ml. of water with stirring. The product was extracted with ether anddried over anhydrous calcium chloride. The ether was evaporated andhexane added to the residue. Upon refluxing a solution was obtainedwhich upon cooling gave a precipitate, 0.5 g. (49% by weight yield) ofthe title compound.

EXAMPLE 5 Preparation of the Compound of Formula (98)

Example 3 was repeated except that 1.0 g. (0.0028 mole) of the oxidizednaphthalidyl-2,6-diisopropyl phenol intermediate was reacted with 0.495g. (0.0028 mole) of 2,6-diisopropyl phenol at room temperature for 6hours in the presence of 15 ml. of phosphorus oxychloride. The resultingsolution was added slowly to a mixture of 100 g. of ice, 50 ml. of waterand 2 ml. of concentrated hydrochloric acid. The oily product wasextracted with ether, dried over anhydrous calcium chloride and theether evaporated. The oil was placed in 50 ml. of hexane and refluxedfor 1 hour. The solution was filtered and the filtrate cooled. Theprecipitate formed upon cooling was collected by filtration and dried togive 0.6 g. (40% by weight yield of title compound, melting range83°-85° C.

EXAMPLE 6 Preparation of the Compound of Formula (171)

(a) 7-carboxyphthalaldehydic acid (5.0 gms., 0.0258 mole) was addedunder nitrogen to 25 ml. of 85% sulfuric acid in a 100 ml. round bottomflask equipped with a stirring bar. Crystalline o-cresol (2.81 gms.,0.0260 mole) was added to the flask with stirring. The resultingorange-pink solution was stirred at room temperature for 6 hours. Thesolution was then poured onto ice (about 50 gms.) with stirring to givea greyish pink mass which was filtered and dried in a vacuum oven at 50°C. The dried solid was recrystallized from methanol with "Norit" toyield colorless needles (4.40 gms., melting point 146° C.).

(b) The product of step a above (0.546 gm., 0.001 mole) was added undernitrogen to a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(0.454 gms., 0.001 mole) in 10 ml. of dichloromethane contained in a 25ml. round bottom flask. The resulting brownish orange solution wasstirred for 4 hours at room temperature. The dichlorodicyanohydroquinoneprecipitate was removed from the solution by filtration, and thedichloromethane was evaporated from the filtrate to give a tan solid.The solid was recrystallized from dichloromethane and hexane andpurified by column chromatography. Elution with dichloromethane andhexane removed a few impurities. Further elution yielded the dehydrointermediate which was recovered as a pink solid (0.440 mg., meltingpoint 220° C. dec.).

(c) The dehydro intermediate of step b (0.270 gm., 0.001 mole) wasdissolved into 10 ml. of ethyl ether in a three neck flask with stirringunder nitrogen. To this solution was added crystalline o-cresol (0.108gm., 0.001 mole) and then 1 ml. of boron trifluoride etherate bydropper. The resulting dark magenta solution was allowed to stand 16hours at room temperature. The ethyl ether was evaporated by a flow ofnitrogen leaving a magenta gum. 10 ml. of ice water was added to thegum. A pink precipitate formed which was removed by filtration anddried. The precipitate was dissolved into 25 ml. of 5% aqueous sodiumhydroxide, and after filtration of the solution, was reprecipitated bythe addition of 5% hydrochloric acid. The off-white precipitate wasfiltered and dried and recrystallized from ethanol containing "Norit" togive the title compound as a white solid (0.220 gm., melting range295°-297° C.).

EXAMPLE 7 Preparation of the Compound of Formula (151)

Following the first two steps of Example 2,2-carboxy-1-naphthol(1-hydroxy-2-naphthoic acid) was reacted withnaphthaldehydic acid to yield the corresponding p-napthalidylnaphtholadduct which then was oxidized to the dehydro intermediate usingo-chloranil. The dehydro intermediate,3-(3'-carboxy-4'-oxo-1'-naphthylidene)naphthalide, was converted to itshydrated form with water. The hydrated intermediate,3-hydroxy-3-(3'-carboxy-4'-hydroxy-1'-naphthyl) naphthalide (about 528mgs.), 1-hydroxy-6-octadecyloxy-2-naphthoic acid (about 480 mgs.) andboron-trifluoride etherate (about 185 mgs.) in glacial acetic acid (12cc.) was refluxed 3 hours. The solution was cooled and evaporated tohalf-volume. On standing a solid formed which was filtered, dried andrecrystallized to give the title compound in about 5% by weight yield.

The last step of Example 7 was repeated using3-hydroxy-3-(3'-carbomethoxy-4'-hydroxy-1'-naphthyl) naphthalide-1,8 asthe hydrated intermediate. The solid formed in the concentrated reactionsolution upon standing was recrystallized from ethanol, and thenhydrolyzed with hot ethanolic sodium hydroxide solution. After coolingto room temperature, the basic solution was acidified with 20%hydrochloric acid. The gum that formed was scratched and triturated withwater until solidification was complete. The solid was air dried anddissolved in boiling cyclohexane. A white solid precipitated from thehot solution almost immediately which was collected and dried to givethe compound of formula 151 in a yield of about 30% by weight.

In addition to the above compounds, the specific indicator dyes offormulae (1) to (19) and (48) above also were prepared in accordancewith the procedure of Example 1. The dye of formula (1) was prepared byreacting indole with the acid, oxidizing the intermediate thus formedand then reacting the oxidized intermediate with ortho-hydroxyphenylindole. In preparing the dyes of formulae (2) to (9), the respective5-substituted indoles were initially reacted with the acid and inpreparing the dyes of formulae (16) to (19), the respective7-substituted indoles were initially reacted with the acid. The dyes offormulae (10) to (15) and (48) were prepared by reacting 7-carboxyindolewith the acid and subsequently reacting the intermediate after oxidationwith the compound selected for the second aromatic nucleus.

It will be appreciated that other phenols, 1-naphthols, indoles andpyrroles substituted in the manner discussed above, for example, withhydrogen-bonding and electron-withdrawing groups and groups useful incontrolling the mobility of the dye product in aqueous solution may besubstituted for the starting materials used in the procedures set out inthe foregoing examples to give the corresponding adduct withnaphthaldehydic, phthaldehydic and carboxyphthaldehydic acid. Followingthe above procedures, the adduct thus obtained may be converted to thecorresponding oxidation product comprising, for example, the compoundsof formulas IIa and IIIa by reacting with a quinone, such as, theo-chloranil or dichlorodicyanobenzoquinone employed above. Alsofollowing the foregoing procedures, the oxidation product may becondensed with the selected aromatic compound, particularly a phenol,1-naphthol, pyrrole or indole substituted as described in the preferredembodiment to yield the indicator dye, either a "mixed" dye or asymmetrical or unsymmetrical indicator.

As noted previously, solvents other than those specified may be used inthe oxidation and the initial and final condensation steps and otheracid condensation catalysts may be employed. Though it is not essential,any one or all of the steps of the process may be carried out in aninert atmosphere, for example, under nitrogen, and final indicator dyesmay be purified by recrystallization from any appropriate solvent or inany other suitable and convenient manner.

Indicator dyes comprising phthaleins containing an indole radical and asecond radical derived from a different N-heterocyclic aryl compound andphthaleins containing an indole radical and a second radical derivedfrom a hydroxy-substituted carbocyclic aryl compound form the subjectmatter of U.S. Pat. Nos. 3,816,120 and 3,816,124, respectively.Indicator dyes containing a naphthalide ring-closing moiety substitutedin the 6-position with certain groups, such as sulfonamido, form thesubject matter of U.S. Pat. No. 3,811,881. Phthaleins derived fromazaphenanthrol form the subject matter of U.S. Pat. No. 3,779,754.Phthaleins containing one phenol radical and a second carbocyclic arylradical, which is different, e.g., a phenyl radical with a differentp-substituent form the subject matter of U.S. Pat. No. 3,782,937.

The indicator dyes produced in accordance with the present invention maybe employed in conventional analytical procedures where phthaleinindicator dyes, such as, phenol phthalide and phenol naphthalide arecommonly used, for example, to measure changes in pH value. The dyesproduced according to the present invention also find other uses.

As discussed in U.S. Pat. Nos. 3,702,244 and 3,702,245, it has beenfound that a selectively exposed photosensitive material having a latentimage therein may be processed in the presence of extraneous incidentradiation actinic thereto by reason of the protection afforded bysuitably positioning with respect to the exposure surface of thephotosensitive layer an effective concentration of a selected dye ordyes as optical filter agents. The use of certain indole dyes includingindole phthalides and naphthalides as optical filter agents forprotecting photosensitive materials from radiation in the shorterwavelength region of the visible spectrum forms the subject matter ofaforementioned U.S. Pat. No. 3,702,244. The use of certain dyes derivedfrom phenols and naphthols including phenol and naphthol phthalides andnaphthalides as optical filter agents for protecting photosensitivematerials from radiation in the longer wavelength region of the visiblespectrum forms the subject matter of aforementioned U.S. Pat. No.3,702,245.

Indicator dyes found particularly useful as optical filter agentsprepared according to the preferred embodiment of the present inventionare phthaleins derived from certain hydroxy-substituted carbocyclic andN-heterocyclic compounds which contain a hydrogen-bonding group, i.e., asubstituent capable of forming a hydrogen-bonded ring with therespective --OH and --NH-- portions of these compounds. Certain indoleand phenolic phthaleins of this type form the subject matter of U.S.Pat. No. 3,862,128. Other phthaleins of this type derived from phenolsand 1-naphthols form the subject matter of U.S. Pat. Nos. 3,833,615 and3,833,614, respectively. Still other phthaleins of this type derivedfrom indoles form the subject matter of copending U.S. patentapplication Ser. No. 409,012, filed Oct. 23, 1973 as acontinuation-in-part of application Ser. No. 108,277, now abandoned.Indoles substituted with selected hydrogen-bonding groups useful in thesynthesis of such indole phthalides and naphthalides form the subjectmatter of U.S. Pat. No. 3,772,329.

Since certain changes may be made in the above processes and productswithout departing from the scope of the invention herein involved, it isintended that all matter contained in the above description shall beinterpreted as illustrative and not in a limiting sense.

What is claimed is:
 1. A compound of the formula: ##STR24## wherein A isselected from ##STR25## and X represents the atoms necessary to completea ring-closing moiety selected from a phthalide and a naphthalide.
 2. Acompound of the formula: ##STR26## wherein A is selected from ##STR27##wherein R¹ is selected from hydrogen, alkoxy containing 1 to 3 carbonatoms and alkyl containing 1 to 3 carbon atoms; R² is selected fromhydrogen, hydroxy, carboxy, sulfonamido, sulfamoyl, o-hydroxyphenyl,bis-trifluoromethylcarbinol, methoxy, alkyl containing 1 to 16 carbonatoms; R³ is selected from hydrogen, alkoxy containing 1 to 18 carbonatoms and alkyl containing 1 to 3 carbon atoms; R⁴ is selected fromhydrogen, hydroxy and carboxy; R⁵ is selected from hydrogen and alkoxycontaining 1 to 18 carbon atoms; and X represents the carbon atomsnecessary to complete a ring-closing moiety selected from phthalide,unsubstituted or substituted in the 4- or 7-position with carboxy, andnaphthalide, unsubstituted.
 3. A compound as defined in claim 2 whereinX represents phthalide.
 4. A compound as defined in claim 2 wherein Xrepresents naphthalide.
 5. A compound as defined in claim 2 wherein A is##STR28##
 6. A compound as defined in claim 2 wherein A is ##STR29## 7.##STR30##
 8. ##STR31##
 9. ##STR32##
 10. ##STR33##